Vascular calcification (VC), the inappropriate deposition of calcium phosphate salts in cardiac valve and vasculature, is increased with aging, certain genetic disorders, valve disease, coronary artery disease, diabetes and chronic kidney disease. Calcification of these normally compliant organs leads to increased stiffness and/or tendency to rupture, and has severe impacts on hemodynamics and cardiovascular function. Despite the recognized deleterious effects of vascular calcium accrual in blood vessels and valves, there are currently no drug therapies available to directly prevent or treat VC. In the past 20 years, Dr. Giachelli's lab has led studies leading to the paradigm-shifting view that VC is a genetically regulated and cell-mediated process, and thus potentially amenable to treatment. These studies have revealed major genetic pathways, cell types and cellular processes that control the initiation and promotion of VC. Moving forward, the challenge is to understand which of these processes is most important under various disease settings, and key mechanistic pathways and/or deficiencies that might be targeted for therapeutic purposes. Thus, the proposed studies focus on understanding the mechanisms by which 1) vascular and valvular cells undergo osteoblast and chondrocyte-like differentiation, 2) phosphate and phosphate transporters regulate VC, and 3) failed anticalcific mechanisms contribute to VC. The proposed studies are an extension of our previous and current work that aim to identify biomarkers, therapeutic targets and therapies to treat this debilitating process.